ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1354C>A (p.Leu452Ile) (rs80358424)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112911 SCV000244420 benign Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0003
Ambry Genetics RCV000561047 SCV000665329 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-19 criteria provided, single submitter clinical testing The p.L452I variant (also known as c.1354C>A), located in coding exon 9 of the BRCA2 gene, results from a C to A substitution at nucleotide position 1354. The leucine at codon 452 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was predicted to be of no clinical significance (IARC Class 1) based on multifactorial likelihood assessment incorporating bioninformatic analysis and segregation information (Whiley PJ et a. PLoS ONE 2014 Jan;9(1):e86836). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000561047 SCV000906886 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-22 criteria provided, single submitter clinical testing This missense variant replaces leucine with isoleucine at codon 452 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000496565 SCV001363258 uncertain significance not specified 2019-08-09 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1354C>A (p.Leu452Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 247634 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1354C>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. The variant has been predicted to be benign based on multifactorial likelihood analysis (Whiley_2014). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two classified as VUS while one classified as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001410482 SCV001612531 likely benign Hereditary breast and ovarian cancer syndrome 2020-08-03 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000112911 SCV000145857 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000112911 SCV000297503 uncertain significance Breast-ovarian cancer, familial 2 2010-11-18 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496565 SCV000587593 uncertain significance not specified 2014-01-31 no assertion criteria provided research

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